Serotonin (5-hydroxytryptamine, 5-HT) regulates a wide variety of sensory, motor and behavioral functions in the mammalian central nervous system (CNS). This biogenic amine neurotransmitter is synthesized by neurons in the raphe nuclei of the brain stem that project throughout the CNS, with highest density in basal ganglia and limbic structures. Steinbusch, Handbook of Chemical Neuroanatomy, 3:68-125, Bjorklund et al., eds., Elsevier Science Publishers, B. V., (1984). Serotonergic transmission is thought to be involved with a variety of behaviors and psychiatric disorders including anxiety, sleep regulation, aggression, feeding and depression. Cowen, British J. Psych., 159:7-14 (1991); and Lucki, Neurosci. & Biobehav. Rev., 16:83-93 (1992). Understanding how 5-HT mediates its diverse physiological actions requires the identification and isolation of the pertinent 5-HT receptors.
Molecular cloning has indicated that 5-HT receptors belong to at least two protein superfamilies: G-protein-associated receptors which have seven putative transmembrane domains (TMDs) (5-HT.sub.1A/B/C/D/E, 5-HT.sub.2 and rat stomach fundus) and ligandgated ion channel receptors which have four putative TMDs (5-HT.sub.3). Albert et al., J. Biol. Chem., 265:5825-5832 (1990); Hamblin et al., Biochem. & Biophys. Res. Comm., 184:752-759 (1992); Adham et al., Molec. Pharm., 41:1-7 (1992); Voigt et al., EMBO J., 10:4017-4023 (1991); Jin, et al., J. Biol. Chem., 267:5735-5738 (1992); Maroteaux, et al., Proc. Natl. Acad. Sci. USA, 89:3020-3024 (1992); Julius, et al., Science, 241:558-564 (1988); Lubbert, et al., Proc. Nat. Acad. Sci. USA, 84:4332-4336 (1987); Hamblin, et al., Mole. Pharm., 40:143-148 (1991); Zgombick, et al., Mole. Pharm., 40:1036-1042 (1991); Weinshank, et al., Proc. Natl. Acad. Sci. USA, 89:3630-3634 (1992); Levy, et al., J. Biol. Chem., 267:7553-7562 (1992); McAllister, et al., Proc. Natl. Acad. Sci. USA, 89:5517-5521 (1992); Pritchett, et al., EMBO J., 7:4135-4140 (1988); Foguet, et al., EMBO J., 11:3481-3487 (1992); and Maricq, et al., Science, 254:432-437 (1991).
As a serotonin receptor cloning strategy, Libert et al., Science, 244:569-572 (1989), demonstrated that novel G-protein-associated receptors could be identified in a polymerase chain reaction (PCR) using degenerate primers corresponding to strongly conserved sequences within their TMDs.
The subtypes of serotonin receptors have been historically distinguished on the basis of their pharmacological binding profiles, on second messenger coupling, and based on physiological roles known for the better characterized serotonin receptors. Most of the characterizing data in the field is not based on the properties of a single purified receptor protein or gene, but rather based on experimental observations using a model tissue. Thus, there is a need for extensive molecular and corresponding pharmacological characterization of serotonin receptors in order to better understand the extent of the subfamilies and the physiological roles each plays.